People and other animals are evolutionarily adapted to live in the context of a 24 hr solar day that is organized into relatively stable periods of ligt and darkness. However, beginning with electrification and bolstered by the information-internet age, deviations from the typical daily pattern of nocturnal sleep and daytime activity have become increasingly common in our society, and daily regular periods of rest and activity have become increasingly unstable. Many people commonly experience day-night disorganization in association with work requirements, care-giving, life style choice, or health conditions. This situation is particularly problematic for individuals who must perform shift work (SW). SW is as common as smoking in Western societies - around 20-25% of the population, is not optional or short-term for many individuals, and is increasingly viewed as a risk factor for many disease conditions. If such associations are confirmed and reflect causality, then even a modest reduction in the detrimental impact of SW could have significant public health benefit. Identifying the long-term health impact of chronic perturbation of the natural diurnal integration of behavior and physiology is crucial to developing sound recommendations and preventive strategies that will protect public health and mitigate disease risk in our increasingly 24/7 society. This R03 grant will test the hypothesis that chronic exposure to repeated diurnal phase shifts (DPS), mimicking SW, will accelerate the disease onset and death in individuals with genetic predisposition to chronic disease. We will test this idea by completing one specific aim: determine whether exposure to life-long repeated DPS/SW will shorten lifespan in strains of mice that are at genetic risk for the development of cancer (AKR/J mice) or autoimmune disease (MRL/MpJ mice). We predict that exposure of AKR/J and MRL/MpJ mice to DPS/SW beginning at 5 weeks of age will accelerate the onset of disease and mortality due to cancer and autoimmune disease, respectively. However, alternative outcomes will also be informative. Growing awareness of the importance of circadian coordination in maintaining health is fostering consideration of diurnal timing in the pathogenesis and treatment of various disease conditions. However, because diurnal tailoring of both life styles and clinical therapies is socially and logistically challenging, clear and unambiguous demonstration of impact will be important in 1) fostering awareness and acceptance of the risks of diurnal asynchrony and 2) developing and implementing strategies to mitigate risk. The prevalence of chronic diurnal disturbance in our society and its associated health risks underscore the need to define the impact of circadian disorganization on the development and progression of chronic diseases. The experiment we propose should provide a powerful platform for further investigation of these important issues.